Background During rapidly evolving outbreaks, health services and essential medical care are interrupted as facilities have become overwhelmed responding to COVID-19. In the Eastern Mediterranean Region (EMR), more than half of countries are affected by emergencies, hospitals face complex challenges as they respond to humanitarian crises, maintain essential services, and fight the pandemic. While hospitals in the EMR have adapted to combat COVID-19, evidence-based and context-specific recommendations are needed to guide policymakers and hospital managers on best practices to strengthen hospitals’ readiness, limit the impact of the pandemic, and create lasting hospital sector improvements towards recovery and resilience. Aim Guided by the WHO/EMR’s “Hospital readiness checklist for COVID-19”, this study presents the experiences of EMR hospitals in combatting COVID-19 across the 22 EMR countries, including their challenges and interventions across the checklist domains, to inform improvements to pandemic preparedness, response, policy, and practice. Methods To collect in-depth and comprehensive information on hospital experiences, qualitative and descriptive quantitative data was collected between May-October 2020. To increase breadth of responses, this comprehensive qualitative study triangulated findings from a regional literature review with the findings of an open-ended online survey (n = 139), and virtual in-depth key informant interviews with 46 policymakers and hospital managers from 18 out of 22 EMR countries. Purposeful sampling supported by snowballing was used and continued until reaching data saturation, measures were taken to increase the trustworthiness of the results. Led by the checklist domains, qualitative data was thematically analyzed using MAXQDA. Findings Hospitals faced continuously changing challenges and needed to adapt to maintain operations and provide essential services. This thematic analysis revealed major themes for the challenges and interventions utilized by hospitals for each of hospital readiness domains: Preparedness, Leadership, Operational support, logistics, supply management, Communications and Information, Human Resources, Continuity of Essential Services and Surge Capacity, Rapid Identification and Diagnosis, Isolation and Case Management, and Infection, Prevention and Control. Conclusion Hospitals are the backbone of COVID-19 response, and their resilience is essential for achieving universal health coverage. Multi-pronged (across each of the hospitals readiness domains) and multi-level policies are required to strengthen hospitals resilience and prepare health systems for future outbreaks and shocks.